Process for continuous sintering of granules

ABSTRACT

The invention relates to a process for continuous sintering of granules for the preparation of pellets, in particular medicament formulations in tablet form.

This application is a 371 of PCT/EP96/02177 filed May 21, 1996.

EP-B-0 043 254 describes a process for the preparation of medicamentformulations with a delayed release of the active compounds which isbased on a selective melting process on at least two lipid or lipoidcomponents which have a retarding action for medicament active compoundsmixed with these components. In these known processes,

(a) the active compound is finely divided,

(b) the finely divided active compound is mixed both with a finelydivided high-melting lipid or lipoid component and with a finely dividedlow-melting lipid or lipoid component, the weight ratio of the two lipidor lipoid components being in the range from 1:5 to 5:1,

(c) the resulting mixture of active compound and lipid or lipoidcomponents is brought to a temperature which is above the melting pointof the low-melting component but below the melting point of thehigh-melting component, the active compound and the high-melting lipidor lipoid component being dispersed uniformly in the completely moltenlow-melting lipid or lipoid component,

(d) after melting of the low-melting component, the resulting mixture iscooled to below the melting point thereof and

(e) the resulting mixture is granulated during cooling or thereafter.

WO-A-93/24110 describes a process for the preparation of sustainedrelease medicament formulations in which the individual components

(i) are extruded as partly molten product through a die plate with theaid of an extruder,

(ii) the extrudate is cooled in the form of strands and

(iii) fed to a granulator and

(iv) the finished granules are subjected to tabletting.

However, according to EP-B-0 043 254, if the low-melting lipid or lipoidcomponent is melted completely, modifications of these components or fatmodifications can form, which can convert back later during storage oftablets which have been prepared using the known granules, such that therelease of the active compound is influenced. In the process known fromWO-A-93/24110, shearing effects can in turn occur, which can lead toabrasion of material in the extruder tube or on the die plate andtherefore to an undesirable introduction of metal into the extrudate.

The object of the present invention is to improve the prior artdescribed.

For this purpose, according to the invention, a process is provided forcontinuous sintering of granules for the preparation of pellets, inparticular medicament formulations in the form of tablets, in which

(a) the individual components are mixed to form a powder,

(b) the powder obtained is introduced in the dry state into an extruder,

(c) the powder introduced is conveyed with the aid of a conveying screwin the direction of the open extruder front or the ejector,

(d) the extruder and/or the screw being heated and one or some of thecomponents being made into a paste or softening (at any rate none of thecomponents melting) and particles of the powder mixture stickingtogether or sintering to form granules,

(e) if appropriate, the sintered granules obtained are sieved and

(f) tabletting is carried out in a manner known per se.

The process claimed thus operates under normal pressure, since a die islacking. The occurrence of shearing forces, as in known extrusion, islargely avoided in this way, so that there is practically no abrasion ofthe extruder tube or on a die provided in the prior art, and thereforeno introduction of metal occurs. Since no single one of the componentsemployed is melted, and since also no strand is extruded, the materialemerging from the extruder in the process according to the invention isobtained as granules, so that it does not have to be subjected to aseparate granulating stage. Instead, the material emerging from theextruder can be sieved, if necessary, the sieve residue being fed totablet making, while the material which passes through the sieve can befed into the process according to the invention again.

A lipid or lipoid component can be used as one of the components for thepowder introduced into the extruder.

Components which include an active compound which has a water-solubilityof greater than 0.5% can be used as starting substances in the processaccording to the invention. Examples of active compounds are Diltiazem,Sotalol, Diclofenac or one of their derivatives, such as Diltiazem.HCl,Sotalol.HCl or Diclofenac sodium.

In the process according to the invention, the extruder and/or the screwcan be heated in zones, three or more zones following one another (inthe conveying direction), the middle zone(s) of which has (have) ahigher temperature than the flanking zones.

According to the invention, a screw in which (in the conveyingdirection), a zone of given thread width and thread pitch is followed bya zone of greater thread width and/or flatter thread pitch. The zones ofdifferent thread width and/or thread pitch can be provided here, forexample, with the aid of individual elements of the screw connected toone another.

According to the invention, two combing screw bodies arranged parallelto one another and running in the same direction or opposite directionscan also be provided as the screw.

The invention is illustrated in more detail by examples below.

EXAMPLE 1

(Diltiazem 90 mg Sustained Release Tablet)

The components of the inner phase were sieved, if necessary, weighed andmixed. The procedure was analogous for the components of the outerphase. The following recipes were chosen here.

    ______________________________________                                        Inner phase  Diltiazem.HCl   90.00                                                         Cutina HR       100.00                                                        Lactose         30.00                                                         Polyvidone      20.00                                                         PEG             20.00                                            Outer phase  Microcrystalline cellulose                                                                    62.00                                                         Na carboxymethyl-starch                                                                       1.70                                                          Highly disperse silicon                                                                       3.30                                                          dioxide                                                                       Magnesium stearate                                                                            3.00                                             Total:                       330.00                                           ______________________________________                                    

The mixture of the inner phase was introduced into the reservoir tank ofan extruder. The extruder was operated without a breaker plate, so thatno pressure built up in the extruder barrel. In the extruder used, fourtemperature zones followed one another in the conveying direction asfollows:

    ______________________________________                                        Zone 1    Zone 2       Zone 3   Zone 4                                        42 ± 5° C.                                                                    68 ± 5° C.                                                                       72 ± 5° C.                                                                   57 ± 5° C.                          ______________________________________                                    

The individual zones were heated up to the stated temperatures, themixture for the inner phase being passed through the extruder after thestated temperatures had been reached. Granules which could be sieved andwere mixed with the mixture for the outer phase were obtained at thedischarge. This mixture was pressed to tablets.

EXAMPLE 2

(Diltiazem 120 mg Sustained Release Tablet)

The procedure was as in Example 1, but the following recipes wereprovided for the inner phase and the outer phase and the followingtemperatures were provided for the four successive temperature zones.

    ______________________________________                                        Inner phase   Diltiazem.HCl 120.00                                                          Cutina HR     46.00                                                           Lactose       208.00                                                          Stearic acid  70.00                                             Outer phase   Hydroxyethylcellulose                                                                       3.20                                                            Magnesium stearate                                                                          1.50                                              Total:                      448.70                                            ______________________________________                                        Zone 1    Zone 2       Zone 3   Zone 4                                        44 ± 5° C.                                                                    69 ± 5° C.                                                                       70 ± 5° C.                                                                   52 ± 5° C.                          ______________________________________                                    

EXAMPLE 3

(Sotalol 240 mg Sustained Release Tablet)

Example 1 was followed, but a 2-layered tablet was prepared with thefollowing recipes and the following temperatures were provided for thesuccessive temperature zones.

    ______________________________________                                        Initial      Sotalol.HCl    40.00                                             layer        Lactose        30.00                                                          Maize starch   30.00                                                          Hydroxypropylcellulose                                                                       3.00                                                           Blue lacquer   0.12                                                           Purified water q.s.                                                                          15.0                                                           Na carboxymethyl-starch                                                       Lactose        35.00                                                          Highly disperse silicon                                                                      1.0                                                            dioxide                                                                       Magnesium stearate                                                                           2.0                                               Total:                      156.12                                            ______________________________________                                        Sustained release layer                                                       Inner phase  Sotalol.HCl    200.0                                                          Lactose        100.0                                                          Cutina HR      140.0                                             Outer phase  Magnesium stearate                                                                           4.0                                               Total                       446.0                                             ______________________________________                                        Zone 1    Zone 2       Zone 3   Zone 4                                        50 ± 5° C.                                                                    71 ± 5° C.                                                                       69 ± 5° C.                                                                   49 ± 5° C.                          ______________________________________                                    

EXAMPLE 4

(Diclofenac 100 mg Sustained Release Tablet)

Example 1 was followed, but the following recipes were provided for theinner phase and the outer phase and the following temperatures wereprovided for the four successive temperature zones.

    ______________________________________                                        Inner phase Diclofenac sodium                                                                              100.00                                                       Sucrose          105.00                                                       1-Hexadecanol    55.20                                            Outer phase Highly disperse silicon diox-                                                                  0.52                                                         ide                                                                           Magnesium stearate                                                                             1.30                                                         Poly-(1-vinyl-2-pyrrolidone)                                                                   1.28                                             ______________________________________                                        Zone 1    Zone 2       Zone 3   Zone 4                                        50 ± 5° C.                                                                    64 ± 5° C.                                                                       63 ± 5° C.                                                                   48 ± 5° C.                          ______________________________________                                    

I claim:
 1. A process for continuous sintering of granules for thepreparation of pellets, comprising:(a) mixing the individual componentsto form a powder; (b) introducing the powder obtained in step (a) in thedry state into an extruder; (c) conveying said powder with the aid of aconveying screw in the direction of the open extruder front; (d) heatingone or both of the extruder or the screw, one or more of the componentsof the powder mixture softening or melting, thereby sintering particlesof the powder mixture together to form granules; and (e) optionallysieving said granules.
 2. A process according to claim 1, wherein alipid or lipoid component is used as one of the components for thepowder.
 3. A process according to claim 1, wherein a pharmaceuticallyactive component having a water-solubility of >0.5% is used as astarting substance.
 4. A process according to claim 2, wherein apharmaceutically active component having a water-solubility of >0.5% isused as a starting substance.
 5. A process according to claim 1, whereinDiltiazem, Sotalol, Diclofenac or a derivative thereof is employed as aportion of said powder.
 6. A process according to claim 2, whereinDiltiazem, Sotalol, Diclofenac or a derivative thereof is employed as aportion of said powder.
 7. A process according to claim 1, wherein oneor both of said extruder or said screw is heated in zones, three or morezones following one another in the conveying direction, the middlezone(s) of which has (have) a higher temperature than the flankingzones.
 8. A process according to claim 2, wherein one or both of saidextruder or said screw is heated in zones, three or more zones followingone another in the conveying direction, the middle zone(s) of which has(have) a higher temperature than the flanking zones.
 9. A processaccording to claim 3, wherein one or both of said extruder or said screwis heated in zones, three or more zones following one another in theconveying direction, the middle zone(s) of which has (have) a highertemperature than the flanking zones.
 10. A process according to claim 5,wherein one or both of said extruder or said screw is heated in zones,three or more zones following one another in the conveying direction,the middle zone(s) of which has (have) a higher temperature than theflanking zones.
 11. A process according to claim 1, wherein a screw inwhich, in the conveying direction, a zone of given thread width andthread pitch is followed by a zone having one or both of a higher threadwidth or flatter thread pitch is employed as said screw.
 12. A processaccording to claim 2, wherein a screw in which, in the conveyingdirection, a zone of given thread width and thread pitch is followed bya zone having one or both of a higher thread width or flatter threadpitch is employed as said screw.
 13. A process according to claim 3,wherein a screw in which, in the conveying direction, a zone of giventhread width and thread pitch is followed by a zone having one or bothof a higher thread width or flatter thread pitch is employed as saidscrew.
 14. A process according to claim 5, wherein a screw in which, inthe conveying direction, a zone of given thread width and thread pitchis followed by a zone having one or both of a higher thread width orflatter thread pitch is employed as said screw.
 15. A process accordingto claim 14, wherein the zones of different thread width or thread pitchare provided with the aid of individual elements of the screw connectedto one another.
 16. The process of claim 1 wherein said extrudercontains two corotating or counterrotating parallel screws.
 17. Aprocess for preparing a pharmaceutical tablet comprising preparing asintered granulate by the process of claim 1 and compressing saidgranulate to form a tablet.